Diversity & racial disparity in fetal membrane cytokine signature during infectio

描述（由申请人提供）：自发性早产（PTB - <妊娠37周前出生）是妊娠的主要并发症，约50%的病例与感染相关。虽然PTB具有多因素病因学，但羊膜内感染（IAI）和由此产生的宿主（母体和胎儿）炎症反应是该疾病的主要组成部分。微生物因素被认为是通过刺激促炎细胞因子和趋化因子的产生而引起一系列事件，这些事件损害了胎儿从受孕到分娩所享有的免疫特权;然而，免疫应答是不可推广的。这表明分娩的开始可能取决于对病原体类型的免疫反应类型。其他组织和细菌因子特异性细胞因子反应也有报道。然而，并非所有的细胞因子似乎都能激活导致分娩和早产的下游介质，这表明从感染到早产的生物分子途径是复杂的，针对早产特定分子机制的患者特异性干预可能是必要的。非洲裔美国人的感染率和PTB发病率不成比例地高于白人，这使得对PTB感染病因学和病理生理学的理解更加复杂。生物标志物浓度的种族差异预计会导致种族差异。此外，羊水由多种抗菌因子组成，并且这些因子的浓度和调节机制也预期在对特定IAI的反应中以及在不同种族中不同。因此，我们假设宿主免疫反应和分娩的生化途径是不可推广的，但与IAI和种族相关的特定细菌之间存在差异。此外，我们假设羊水的免疫调节作用也依赖于细菌种类和母体种族。我们将通过以下具体目标来检验我们的假设：具体目标1：通过暴露于常见羊膜内病原体的正常人胎膜来检验TH 1/TH 2和促炎细胞因子/趋化因子（IL-8）反应和动力学的差异，所述常见羊膜内病原体包括：微小脲原体、人型支原体、E.大肠杆菌、B群链球菌、牙龈卟啉单胞菌和G.流浪汉具体目标二：为了确定是否有种族差异，在TH 1/TH 2细胞因子签名产生的胎膜响应于上述目标1中列出的细菌物种。具体目标3：测试羊水在维持平衡的细胞因子反应中的抗炎特性。 公共卫生相关性：由TH 1/TH 2细胞因子模式转换介导的有利于促炎反应的羊膜腔内微生物侵入和羊膜内感染和炎症通常与自发性早产相关。非裔美国人的感染率和早产率不成比例地更高，感染相关早产率增加，表明感染相关的病理生理途径和生物标志物可能不可推广，每种细菌可能产生其自身的炎症特征，种族差异将与生物标志物特征相关。在该RO 3申请中，计划使用用于胎膜的体外器官外植体系统进行试点研究，我们计划测试与常见羊膜内病原体相关的差异性炎症反应和种族差异。

DESCRIPTION (provided by applicant): Spontaneous preterm birth (PTB - <birth before 37 weeks gestation) is a major complication of pregnancy and infection is associated with ~ 50% of the cases. Although PTB has a multifactorial etiology, intraamniotic infection (IAI) and the resulting host (maternal and fetal) inflammatory response is a major component of the disease. Microbial factors are thought to evoke a series of events that compromise the immunological privileges that the fetus enjoys from conception until parturition by stimulating the production proinflammatory cytokines and chemokines that induce labor; however, the immune response is not generalizable. This suggests that initiation of labor may depend on the type of immune response to the type of pathogen. Other tissue and bacterial factor-specific cytokine response have also been reported. Not all cytokines, however, seem to activate the downstream mediators that cause labor and preterm birth suggesting that the biomolecular pathways from infection to preterm birth are complex and that patient-specific interventions targeted to a particular molecular mechanism of preterm birth may be necessary. Understanding the infectious etiology and pathophysiology of PTB is further complicated by disproportionately higher rate of infection and PTB rates in African-Americans than Caucasians. Racial differences in biomarker concentrations are expected to contribute to racial disparity. Furthermore, amniotic fluid consists of multiple antimicrobial factors and the concentration and regulatory mechanisms of these factors are also expected to differ in response to specific IAI and also in different races. Therefore, we hypothesize that host immune response and biochemical pathways of labor are not generalizable but differ between specific bacteria associated with IAI and race. In addition, we hypothesize that the immunomodulatory effects of amniotic fluid is also dependent on bacterial species and maternal race. We will test our hypotheses through the following specific aims; Specific Aim 1: To test the differences in the TH1/TH2 and proinflammatory cytokine/chemokine (IL-8) response and kinetics by normal human fetal membranes exposed to common intraamniotic pathogens including: Ureaplasma parvum, Mycoplasma hominis, E. coli, Group B Streptococcus, P. gingivalis and G. vaginalis. Specific Aim 2: To determine if there are racial differences in TH1/TH2 cytokine signature produced by fetal membranes in response to bacterial species listed above in Aim 1. Specific Aim 3: To test the anti-inflammatory properties of amniotic fluid in maintaining a balanced cytokine response. PUBLIC HEALTH RELEVANCE: Microbial invasion of the intraamniotic cavity and intraamniotic infections and inflammation mediated by a switch in the TH1/TH2 cytokine pattern favoring a proinflammatory response are commonly associated with spontaneous preterm birth. Disproportionately higher rate of infection and preterm births in African Americans and increasing rate of infection associated preterm birth suggest that the infection associated pathophysiologic pathways and biomarkers may not be generalizable and each bacterium may produce their own inflammatory signature and racial disparity will be associated with biomarker profile. In this RO3 application, a pilot study is planned using an in vitro organ explant system for fetal membranes we plan to test differential inflammatory response and racial disparity associated with common intraamniotic pathogens.